Interleukin 27 (IL-27) is a pleiotropic cytokine that was initially shown to promote Th1 differentiation while antagonizing Th17 development during Ag priming phase of the immune response. However, an emerging paradigm is that IL-27 activates c-Maf leading to the up-regulation of Aryl hydrocarbon receptor, culminating in sustained expression of IL-10 that promote development of Tr1 cell. Our previous work showed that (i) IL-27 is constitutively expressed in retinal ganglion and photoreceptor cell layers and that the up-regulation of IL-27 by retina cells inhibits proliferation of Th17-cells during EAU. We suggested a mechanism by which Th1 cells mitigate uveitis by antagonizing Th17 expansion through IFN-g-mediated induction of IL-27 in target tissue. During this review period, our investigation focused on: (a) identifying retinal cells that produce IL-27 and retinal cells that express the IL-27 receptor and respond to IL-27; (b) examining potential physiological benefits of constitutive secretion of IL-27 by retinal cells. Our studies revealed the following: (i) That microglia cells in the neuroretina constitutively secrete IL-27 and up-regulated their expression of IL-27 during uveitis. (ii) Photoreceptors constitutively express IL-27 receptor and responded to IL-27 signaling by producing anti-inflammatory molecules through STAT1-dependent mechanisms. (iii) Suppression of EAU was mediated through IL-27-induced production of IL-10, SOCS1 and SOCS3 by retinal cells and the SOCS proteins protected retinal cells from cytokine-mediated apoptosis. Taken together, these studies suggest that IL-27 may be beneficial in the treatment of CNS inflammatory diseases, such as, uveitis and multiple sclerosis.